Peptides synthesized from the CDR3 region of CD4, when appropriately derivatized, are anti-HIV antivirals. The prototype compound TIC4E5- tribenzyl-K10-acetyl-TYICEVEDQKEE inhibited HIV-1-induced cell fusion at 32 microM, HIV-1 infection of CEM-SS cells at 10 microM, SIV infection of CEM- 174 cells at less than 125 microM, gp120/CD4 binding at 60 microM, post infection cell-mediated viral transmission at 10-15 microM, and gp 120 stripping from the envelope glycoprotein complex at 200 microM. Activity of various substituted and derivatized congeners indicated that the CD4 (81-92) organopeptides most likely possess antiviral activity by virtue of conformational approximation to the CDR3-homologous gp 120 binding site of the native CD4 molecule. Peptide antiviral activity was specific, as judged by lack of cytotoxicity, lack of specific inhibition of HTLV-1 induced cell fusion, and lack of inhibition of CD4-dependent cellular immune function in vitro. Cyclic congeners yielded peptides with sub micromolar potency to block HIV-1 infection. During the course of employing SIV-infected rhesus macaques to assess peptide safety and efficacy, animals were longitudinally tested on a battery of neurocognitive and motor tasks to determine if the SIV-infected rhesus macaque can be used as a model for HIV-associated CNS disease and dysfunction. Three of ten SIV-infected animals, all within the subgroup of those with most active ongoing infection (as judged by viral antigenemia and virus rescue from peripheral blood mononuclear cells), showed relatively large decrements in performance in either motor skill or delayed matching to sample cognitive tests, demonstrating that the SIV-infected rhesus monkey is a model for HIV-associated motor/cognitive complex (AIDS dementia complex) as well as acquired immunodeficiency syndrome itself. All of the productively infected animals surviving past ten months post- inoculation showed a group significant decrement in motor skill performance prior to the onset of clinical signs of immunodeficiency disease. Evidence of decrements in cognitive function were obtained in infant rhesus macaques inoculated within 72 hours of birth with SIV, except that these animals had a more rapid course of disease and more profound drop in CD4-positive cell than the juvenile animals.